Measurement of apolipoproteins can be achieved by sensitive radioimmunoassays. However, the assays have been hampered for many years because lipids usually interfere the immunoreactivity of the apoproteins. It is very difficult to standardize the radioimmunoassays due to the heterogeneity of the antibodies. It is well established now that a given pure protein antigen will usually produce a mixed population of the antibodies, i.e., the pure apoprotein contains more than one antigenic determinant. In particular, each determinant of the apoprotein may interact with antibodies to a differential degree in the presence of lipids. Theoretically and technically this problem can be overcome by chemically or physically modifying the radioimmunoassay procedures or by using selected antibody populations. A major advancement in molecular immunology has been the introduction of techniques for the production of homogeneous monoclonal antibodies. It is now possible to sort mixed antibody populations to select an antisera that reacts with one antigenic determinant of an antigen at a time. The pure monoclonal antibodies can be artificially obtained from hybridomas which are derived from antibody producing cells which are fused with a mouse myeloma cell. We are particularly interested in choosing specific monoclonal antibodies which can recognize the "surface" determinants of apolipoproteins in lipoprotein particles. Since many monoclonal antibody lines can be generated, we cannot begin to screen the specific lines without some knowledge of the antigenic structures of the apolipoproteins. Our short-term goals for the present studies are to: a) study the antigenic structure of apolipoproteins and lipoproteins; b) modify the radioimmunoassays (RIA) by chemical means; c) isolate specifically selected antibody populations for RIAs; d) apply the technique to the study of lipoprotein metabolism in normal subjects and in patients with different forms of primary and secondary hyperlipoproteinemia; and e) develop hybridoma monoclonal antibodies for apoA-I and apoA-II. Long-term goals will be to: a) further explore the antigenic structure of apolipoproteins and lipoproteins; b) develop the monoclonal antibodies against LDL, HDL, apo E, apoC-II, and apoC-III in addition to apoA-I and apoA-II; and c) use the monoclonal antibodies to study the molecular function of apoproteins and lipoproteins.